Project Summary/Abstract This project describes the discovery and characterization of a novel human microprotein that functions in cellular RNA decay. RNA decay, or turnover, is a critical mechanism of post-transcriptional gene expression regulation, degrading not only normal cellular RNA at the end of its lifetime, but also disease-related mRNAs that are degraded to prevent production of toxic, mutant proteins. Our novel polypeptide, which we term NoBody for ?non-annotated P-body associated polypeptide?, is translated from a long non-coding RNA. NoBody is only 7 kDa in size, and is intrinsically disordered. Despite its lack of structure, NoBody is highly conserved in mammals, and we show that it specifically interacts with proteins involved in the first step of a key RNA turnover pathway ? mRNA decapping ? and that it is linked to the abundances of hundreds of cellular transcripts. We propose to elucidate the biochemical function and structure of this microprotein in complex with mRNA decapping proteins, as well as the genes and biological processes that are under its control. The significance of this proposal is that we will reveal an entirely novel mechanism of regulation of mRNA decay ? modulation of mRNA decapping by a previously unknown microprotein. More broadly, this work will demonstrate that innovative, proteomics-based platforms for new gene discovery have the potential to reveal new molecular players in important cellular processes and disease.